Multiple myeloma (MM) is a devastating bone marrow (BM) cancer that remains uniformly fatal despite the emergence of novel therapeutics. The tumor microenvironment promotes tumor growth and resistance to chemotherapy through poorly understood interactions between tumor cells and the surrounding BM cells. We have recently demonstrated that a population of BM myeloid-derived suppressor cells is involved in regulation of MM progression. These cells abundantly produce the pro-inflammatory protein S100A9. Our preliminary data indicate that this protein regulates MM survival and growth, and we hypothesize that this effect is at least partially mediated by a direct effect of S100A9 in increasing megakaryopoiesis, and that increased production of angiogenic factors by megakaryocytes and platelets leads to increased BM angiogenesis and tumor progression. We propose to test this hypothesis by determining the molecular effects of S100A9 on megakaryocytes and by testing a novel S100A9 inhibitor in models of MM to see if it reduces megakaryopoiesis and angiogenesis and thereby improves MM outcomes. The following specific aims will be addressed: Specific Aim 1. To determine the molecular mechanisms underlying the effect of S100A9 on megakaryocytes; Specific Aim 2. To investigate the role of S100A9 as a novel therapeutic target in MM.